The objective of the proposed studies is to elucidate the relationship between the observed abnormalities in the alpha 2-macroglobulin-protease complex in patients with cystic fibrosis and the clinical manifestations of this disease. In order to accomplish this objective, it will be necessary to determine the specificity of the defect in alpha 2-macroglobulin-trypsin complex in cystic fibrosis, determine molecular differences in purified normal and cystic fibrosis alpha 2-macroglobulin, develop more precise quantitative assays for alpha 2-macroglobulin and alpha 2-macroglobulin-protease complex determination, and develop more accurate methods to determine protease activities in plasma, cultivated fibroblasts, cultivated amniotic fluid cells, white blood cells and amniotic fluid. The successful application of these techniques may well provide a specific biochemical marker which will be of value not only for the detection of cystic fibrosis but for the accurate identification of heterozygotes, the in utero detection of this disease, and possibly the development of rational approaches to more precise therapy than exists at the present time.